ABSTRACT The blood brain barrier (BBB) plays a key role in maintaining brain integrity. The BBB prevents unwanted molecules from entering the brain and supplies essential nutrients and signaling molecules to meet the high- energy demand of neurons. Specialized brain endothelial cells (BECs) are central to the function of the BBB. BECs express tight junction proteins that limit paracellular permeability to factors from the blood and BECs form an extensive network with every neuron supplied by its own capillary. Current research has demonstrated that BEC dysfunction is prevalent in aging leading to both higher leakiness and lower vessel coverage. These changes may affect cognition in two ways: 1) Higher BEC leakiness to plasma proteins can lead to damage of neurons directly or through bystander effects (e.g. glial mediated neuroinflammation) and; 2) Lower vessel coverage limits the supply of essential nutrients to neurons. An important question is the extent and underlying mechanism(s) that genetic factors risk factors for cognitive decline in aging modulate BEC function. One such factor is APOE genotype, as APOE4 is associated with cognitive dysfunction compared to APOE3 in older adults. Our in vivo data supports that APOE4 is associated with BEC dysfunction in aging, and a potential underlying mechanism has emerged. Angiogenic growth factors are important for controlling leakiness and maintaining vessel coverage through actions on BEC function. Our data suggest a mechanistic interaction exists between APOE and epidermal growth factor (EGF) pathways. Specifically, that apolipoprotein (apoE) E3 produced by BECs signals in an autocrine/paracrine-like manner via apoE receptors to increase the production of EGF, resulting in improved BEC function. However, this process is impaired with apoE4. Based on these data, we propose to test the hypothesis that failure in apoE4 receptor signaling leads to BEC dysfunction and that EGF can ameliorate this dysfunction. We further propose that this mechanism contributes to BEC dysfunction observed in Alzheimer's disease (AD) patients. APOE4 is the greatest genetic risk for sporadic AD, increasing risk up to 12-fold compared to APOE3 and high levels of amyloid-?(A?) in the brain are a major component of AD. Our preliminary data suggest A? exacerbates APOE4 associated BEC dysfunction. Thus, our experiments will evaluate whether APOE4 increases BEC dysfunction and whether A? exacerbates this dysfunction in vivo. We will examine the possibility that a failure in apoE receptor signaling underlies BEC dysfunction with apoE4, and that this disruption is exacerbated by A?. Finally, we will test whether peripheral administration of EGF reduces deficits in BEC and cognitive function. Our studies would implicate apoE4 associated BEC dysfunction as an important pathway contributing to cognitive decline in both aging and AD